Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib.

INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

The risk of hospitalisation from RSV is not increased by co-infection in children under 24-months-of-age.

The recent pandemic prompted renewed interest in paediatric respiratory infections, including whether co-infections - particularly with RSV - have an adverse prognostic impact. We evaluated the charts of all children presenting with respiratory symptoms to our unit between October 2022 and April 2023, each of whom was subjected to a multiplex PCR assay to detect eight viral targets and one bacterial target and examine the relationships between mono- and co-infections and hospitalization outcomes. We observed that younger age and RSV infection were both associated with the need for hospitalisation and the duration of hospitalisation after adjusting for confounders. Co-infection was, however, not associated with these outcomes.   Conclusion: This real-world data add to a growing consensus that RSV increases the risk of hospitalisation, while other co-infections, except for co-infection with SARS-CoV-2, do not. Given the timeframe over which our study was conducted, only a few children had SARS-CoV-2 co-infection, so we could not confirm any significant effect from this interaction. What is Known: • RSV increases the risk of hospitalisation and the need tor ventilatory support, especially in very young children. What is New: • Younger age and RSV infection were both associated with the need for hospitalisation and the duration of hospitalisation after adjusting for confounders. • Co-infection was, however, not associated with these outcomes.

A rare rarity: Neuroendocrine tumor of the esophagus.

Esophageal Neuroendocrine tumors (NETs) are rare, aggressive and lacking specific symptoms. This causes a diagnostic delay, worsening the prognosis. Numerous cases are reported in literature, without a consensus on the management. Our aim was to clarify epidemiology, clinical presentation, diagnostic, therapeutic management of esophageal NETs. Extensive literature search identified a total of 226 articles. One hundred twenty-five articles (n = 1676) met the inclusion criteria, showing that: the incidence of esophageal NET varies geographically; men (60-70 years) are more affected; smoking and alcohol abuse are the major risk factors; dysphagia, weight loss, appetite loss are the most common clinical features. The histotypes include high-grade small and large cell esophageal carcinomas and low-grade carcinoid tumors. Mixed neuroendocrine/non-neuroendocrine neoplasms are the most common. Often the diagnosis occurs randomly on endoscopic examination. Circulating markers, functional combined with conventional imaging contributes to the diagnosis and management. Treatment depends on type, grade and stage of the tumor.

Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors.

Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy.

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives.

PURPOSE: Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate. METHODS: With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic. RESULTS: We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines. CONCLUSIONS: Our critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.

Ultrasound features of medullary thyroid carcinoma correlate with cancer aggressiveness: a retrospective multicenter study.

BACKGROUND: Poor prognosis of medullary thyroid cancer (MTC) with suspicious ultrasound (US) features has been reported. The aim of the study was to investigate the association between preoperative US presentation and aggressiveness features of MTC. Also, US features of MTC were compared with those previously reported. METHODS: Study group comprised 134 MTC from nine different centers. Based on US presentation the nodules were stratified in "at risk for malignancy" (m-MTC) or "probably benign" (b-MTC) lesions. RESULTS: Eighty nine (66.4%) m-MTC and 45 (33.6%) b-MTC were found. Metastatic lymph nodes (p = 0.0001) and extrathyroid invasiveness (p < 0.0001) were more frequent in m-MTC. There was statistically significant correlation (p = 0.0002) between advanced TNM stage and m-MTC with an Odds Ratio 5.5 (95% CI 2.1-14.4). Mean postsurgical calcitonin values were 224 ± 64 pg/ml in m-MTC and 51 ± 21 in b-MTC (p = 0.003). CONCLUSIONS: This study showed that sonographically suspicious MTC is frequently associated with features of aggressiveness, suggesting that careful preoperative US of MTC patients may better plan their surgical approach.

Relationship between growth hormone/insulin-like growth factor-1 axis integrity and voluntary weight loss after gastric banding surgery for severe obesity.

BACKGROUND: The aim of this observational study was to determine, in a retrospective analysis, whether growth hormone (GH) and insulin-like growth factor-1 (IGF-1) at baseline or changes in the GH/IGF-1 axis after laparoscopic adjustable gastric banding (LAGB) is associated with weight loss and body composition changes in severely obese nondiabetic patients. METHODS: Weight loss (expressed as percent excess weight loss [EWL%]), anthropometry, body composition by bioelectrical impedance analysis (BIA), serum IGF-1, and GH peak after GH-releasing hormone (GHRH) plus arginine (ARG) test were measured and expressed as standard deviation scores (SDS) of reference values in 104 women and 36 men, age (mean +/- SD) 34 +/- 11 and 30.2 +/- 11 years, and BMI 44 +/- 5.7 and 39 +/- 3.2, respectively, before and 6 months after LAGB. RESULTS: After LAGB, 25% of women and 22.5% of men had GH deficiency, while 30.8% of women and 33.3% of men had IGF-1 deficiency or insufficiency. The median EWL was 36.8% in women and 40.0% in men. In both genders, percent decrease of waist circumference, EWL, and fat mass (FM) and percent increase of fat-free mass (FFM) was greater in patients with normal GH secretion and IGF-1 levels. The GH peak after GHRH + ARG, IGF-1 levels, and IGF-1 SDS were inversely correlated with EWL% (r = -0.50, r = -0.53, and r = -0.42, respectively; p < 0.0001) and percent FM (r = -0.41, r = -0.36, and r = -0.35, respectively; p < 0.0001). In stepwise linear regression analysis, the GH peak after GHRH + ARG was the major determinant of EWL% (p < 0.0001) and FM (p = 0.001). CONCLUSIONS: The efficacy of LAGB was greater in the patients with a normal GH response to GHRH + ARG and with normal IGF-1 levels. The percent of FM, FFM, and EWL were significantly correlated with the GH response to GHRH + ARG and with IGF-1 levels.

A reappraisal of diagnosing GH deficiency in adults: role of gender, age, waist circumference, and body mass index.

OBJECTIVE: The objective of the study was to reevaluate the diagnostic accuracy of GH peak after GHRH plus arginine test (GHRH+ARG) according to patients' age, body mass index (BMI), and waist circumference to diagnose GH deficiency (GHD). OUTCOME MEASURES: GH peak after GHRH+ARG and IGF-I levels reported as sd score. SUBJECTS: Subjects included 408 controls (218 women, 190 men, aged 15-80 yr) and 374 patients with hypopituitarism (167 women, 207 men, aged 16-83 yr). RESULTS: In the (elderly) healthy subjects 15-25 yr old (young), 26-65 yr old (adults) and older than 65 yr, GH cutoffs were 15.6, 11.7, and 8.5 microg/liter, 11.8, 8.1, and 5.5 microg/liter, and 9.2, 6.1, and 4.0 microg/liter, respectively, in the lean, overweight, and obese subjects. Waist circumference was the best predictor of GH peak (t = -7.6, P < 0.0001) followed by BMI (t = -6.7, P < 0.0001) and age (t = -5.7, P < 0.0001). Based on the old (<9.1 microg/liter) and new GH cutoff, 286 (76.5%) and 276 (73.8%) of 374 hypopituitary patients had severe GHD. The receiving-operator characteristic analysis showed GH cutoffs in line with the third percentile or slightly higher results so that the prevalence of GHD increased to 90.1%. CONCLUSIONS: The results of the current study show that waist circumference and BMI are the strongest predictors of GH peak after GHRH+ARG followed by age. However, the old cutoff value of 9.0 microg/liter was in line with the new cutoffs in 95% of patients.

Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone deficiency.

BACKGROUND: Severe GH deficiency (GHD) is associated with, increased cardiovascular risk and intima-media thickness (IMT) at major arteries. OBJECTIVE: The objective of the study was to investigate the 5-yr effects of GH replacement on common carotid IMT and insulin resistance syndrome (IRS) (at least two of the following: triglycerides levels > or = 1.7 mmol/liter, high-density lipoprotein-cholesterol levels < or = 1.0 mmol/liter, blood pressure above 130/85 mm Hg, fasting glucose 6.1-7 or 2 hr after glucose 7.7-11.1 mmol/liter). DESIGN: This was an interventional, open, prospective, controlled study. PATIENTS: Patients included 35 men with severe GHD and 35 age-matched healthy men as controls. INTERVENTION: All patients received standard replacement therapy; GH replacement was added in 22 patients (group A) and refused by 13 others (group B). MEASUREMENTS: Five-year changes in IMT and IRS prevalence were measured. RESULTS: At baseline, IMT was higher in the patients with (P < 0.001) and without IRS (P = 0.004) than in controls. Eighteen patients (51.4%) and two controls (5.7%; P < 0.0001) had IRS. At study end, use of lipid-lowering drugs (92.3, vs. 13.6 and 34.3%, P < 0.0001), glucose-lowering drugs (69.2 vs. 31.4 and 22.7%; P = 0.016), and antihypertensive drugs (61.5 vs. 20.0 and 4.5%; P < 0.0001) was higher in group B patients than controls and group A patients. IGF-I levels normalized in all group A patients and remained lower than -1 sd score in 77% of group B patients. IMT significantly decreased only in group A and significantly increased in controls and nonsignificantly in group B patients. IRS prevalence significantly reduced only in group A patients. CONCLUSIONS: Severely hypopituitary GHD men have more frequently increased IMT at common carotid arteries and IRS than controls. After 5 years, only in GH replaced patients, IMT and prevalence of IRS decreased.

GH and IGF-I deficiency are associated with reduced loss of fat mass after laparoscopic-adjustable silicone gastric banding.

CONTEXT: GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF-I axis after laparoscopic-adjustable silicone gastric banding (LASGB) are associated with changes of body composition. OBJECTIVE: To analyse the relationships between changes in the GH/IGF-I axis and those of body weight and composition before and after LASGB. DESIGN: Observational, prospective. SETTING: University 'Federico II' of Naples (Italy). PATIENTS: Seventy-two severely obese females (BMI: 44.9 +/- 4.68; mean age: 33.1 +/- 11.34 years) were studied. MAIN OUTCOME MEASURES: GH peak after GHRH plus arginine test, IGF-I, IGFBP-3 and ALS levels, fat mass (FM) and free fat mass (FFM) (by Bioelectrical Impedance Analysis) at baseline and 6 months after LASGB. The change in percentage of individual variables was calculated as well as that of excess of body weight loss (EBWL%). The FM%, FFM% and EBWL% were correlated with peak GH and IGF-I levels changes. RESULTS: At baseline, GH deficiency (GHD) (GH peak = 4.1 microg/l) was found in 22 patients (31%), 16 of them also had IGF-I deficiency (< -2SDS). IGF-I levels were inversely correlated with waist circumference (r = -0.72, P < 0.001) and FM% (r = -0.75, P < 0.001). Post-LASGB the patients were classified as follows: group (1) GH and IGF-I sufficient (n = 44; 61.1%); group (2) GH and IGF-I deficient (n = 14; 19.4%) and group (3) GH sufficient and IGF-I deficient (n = 14; 19.4%). The percentage changes of EWBL (P < 0.05, P = 0.051, respectively) and FM (P < 0.001, P < 0.01, respectively) were lower in groups (2) and (3) than in group (1). At the stepwise linear regression analysis, postoperative IGF-I levels were the strongest determinant of percent changes of FM (P < 0.0001), of FFM (P = 0.009) and of EBWL (P < 0.0001). CONCLUSIONS: IGF-I levels is the most sensitive to unfavourable changes in body composition 6 months after LASGB making investigation of the somatotropic axis useful in the evaluation of bariatric surgery outcomes.

The natural history of partial growth hormone deficiency in adults: a prospective study on the cardiovascular risk and atherosclerosis.

BACKGROUND: Partial GH deficiency (GHD) in adults is poorly studied. OBJECTIVE: The objective of the study was to investigate the natural history and clinical implications of partial GHD. STUDY DESIGN: This was an analytical, observational, prospective, case-control study. PATIENTS: Twenty-seven hypopituitary patients (15 women, ages 20-60 yr) and 27 controls participated in the study. MAIN OUTCOME MEASURES: Measures included GH peak after GHRH plus arginine [(GHRH+ARG), measured by immunoradiometric assay]; IGF-I (measured after ethanol extraction) z-sd score (SDS); glucose, insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels; and common carotid arteries intima-media thickness (IMT) measured periodically. RESULTS: At study entry, partial GHD patients had significantly lower IGF-I and HDL-cholesterol levels and homeostasis model assessment index than controls. During the 60 months of median follow-up, 11 patients had severe GHD (40.7%), seven normalized their GH response (25.9%), and nine showed persistently partial GHD (33.3%). Patients with developed severe GHD at baseline had similar age and body mass index and lower GH peak (11.5 +/- 1.8 vs. 14.3 +/- 1.5 and 12.8 +/- 1.1 microg/liter, P = 0.008) and IGF-I SDS (-0.88 +/- 0.48 vs. 0.15 +/- 0.58 and -0.42 +/- 0.78; P = 0.01) than the patients with normal GH secretion or partial GHD. Severe GHD was accompanied by decreased IGF-I SDS and increased total to HDL cholesterol ratio, triglycerides, homeostasis model assessment index, and carotid intima-media thickness; normalization of GH secretion was accompanied by increased IGF-I SDS. By receiving-operator characteristic analysis, predictors of severe GHD were a baseline GH peak after GHRH+ARG of 11.5 microg/liter (sensitivity 64%, specificity 94%) and a baseline IGF-I SDS of -0.28 (sensitivity 91%, specificity 63%). CONCLUSIONS: Of 27 patients with partial GHD after pituitary surgery, 40.7% developed severe GHD and 25.9% normalized their GH response. With the assay used, changes in the GH peak response to GHRH+ARG were accompanied by changes in the IGF-I SDS, metabolic profile, and carotid IMT. A peak GH of 11.5 microg/liter or less and IGF-I SDS -0.28 or less were highly predictive of delayed deterioration of GH secretion.

Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a two-year open, prospective study in young adult men and women with severe GH deficiency.

CONTEXT: GH secretion and response to GH replacement are gender-related. OBJECTIVE: The objective of this study was to investigate the effects of GH deficiency (GHD) and replacement on the cardiovascular system according to gender. DESIGN: The design was open and prospective. SETTING: The study was conducted at a university hospital. SUBJECTS: Subjects included 36 severe adult-onset GHD patients (18 men, 20 women, aged < 45 yr); 36 gender-, age-, and body mass index-matched healthy subjects served as controls. INTERVENTIONS: Subjects received GH replacement at a median dose of 6.5 microg/kg.d in men and 7.7 microg/kg.d in women for 2 yr. MAIN OUTCOME MEASURES: Homeostasis model assessment index, total to HDL cholesterol ratio, fibrinogen and C-reactive protein levels, left ventricular mass index, blood pressure, heart rate, diastolic filling, and systolic function at rest and at peak exercise and intima-media thickness (IMT) at common carotid arteries were measured. RESULTS: Basal prevalence and/or degree of insulin resistance, lipid alterations, compromised cardiac function, and IMT were similar in women and men. Diastolic dysfunction was more prevalent in men (61 vs. 25%, P = 0.036). After GH replacement, IGF-I levels normalized in all patients. Lipid profile, fibrinogen, and C-reactive protein levels normalized in all cases. The total to HDL ratio (P = 0.04) was higher in women than men. The homeostasis model assessment index persisted higher in GHD patients than controls and decreased only in GHD men (P = 0.017). Left ventricular mass index normalized during treatment in both women and men, abnormal diastolic function persisted in three women (P = 0.031), and abnormal systolic performance persisted in six women and one man (P = 0.13). IMT decreased similarly in women and men, persisting higher than in controls. Exercise performance normalized in all. CONCLUSIONS: Two-year GH replacement has similar beneficial effects on cardiac and exercise performance and atherosclerosis in women and men with severe GHD.

Common carotid intima-media thickness in growth hormone (GH)-deficient adolescents: a prospective study after GH withdrawal and restarting GH replacement.

We prospectively investigated the risk of early atherosclerosis, by classical cardiovascular risk factors and intima-media thickness (IMT) at the common carotid arteries, in 23 adolescents diagnosed as GH deficient (GHD) during childhood and in 23 healthy sex-, age-, and BMI-matched controls. Measurements were performed in all subjects before stopping GH replacement. Because the diagnosis of GHD had been confirmed in 15 of the 23 adolescents, the protocol changed according to the diagnosis as follows: measurements were repeated after 6 months of GH withdrawal and 6 months of GH reinstitution in the 15 with GHD, and after 6 and 12 months of GH withdrawal, measurements were also taken in the eight non-GHD subjects. Serum IGF-I levels were in the normal range for age in all patients before GH withdrawal. When compared with controls, before GH withdrawal, GHD adolescents had reduced high-density lipoprotein cholesterol levels and increased total/high-density lipoprotein cholesterol ratio, fibrinogen, low-density lipoprotein cholesterol, and glucose levels; non-GHD adolescents had increased glucose, insulin, and homeostasis model assessment score. IMT at the common carotid arteries was similar in GHD and controls (0.52 +/- 0.03 vs. 0.55 +/- 0.06 mm; P = 0.23) and was higher in non-GHD than in controls (0.62 +/- 0.03 vs. 0.54 +/- 0.06 mm; P = 0.01). In GHD adolescents, 6 months of GH treatment withdrawal and 6 months of GH treatment reinstitution modified IGF-I levels, lipid profile, and insulin resistance but not IMT or systolic and diastolic peak velocities at the common carotid arteries. In non-GHD subjects, 12 months of GH treatment withdrawal significantly decreased IGF-I levels, IMT (to 0.54 +/- 0.06 mm; P < 0.001 vs. baseline), systolic and diastolic peak velocities, and improved insulin resistance. In conclusion, the discontinuation of GH in confirmed GHD adolescents is not followed by significant alterations of the common carotid arteries, despite the profound negative alterations of the lipid profile. In adolescents who were not confirmed to have GHD, IMT was increased while on GH therapy and normalized when they were taken off of GH.

Short-term effects of growth hormone (GH) treatment or deprivation on cardiovascular risk parameters and intima-media thickness at carotid arteries in patients with severe GH deficiency.

To explore early effects of GH treatment or deprivation on cardiovascular risk factors and carotid intima-media thickness (IMT), we designed this randomized, cross-over study in 34 adult patients with severe GH deficiency. At study entry, the patients were randomized into two groups (A and B); group A (n = 17) received appropriate replacement therapy including GH at standard doses for 6 months and then were withdrawn from GH for the subsequent 6 months; group B (n = 17) received appropriate replacement therapy excluding GH for 6 months with the addition of GH in the subsequent 6 months. After the first 6 months, we observed a significant increase in IGF-I levels and of high-density lipoprotein (HDL)-cholesterol together with a significant decrease in diastolic blood pressure, the total/HDL-cholesterol ratio, and C-reactive protein in the patients in group A, whereas vascular parameters did not significantly change. In the patients in group B, none of the parameters studied significantly changed. After 6 months of GH withdrawal in the patients in group A, a significant decrease in IGF-I levels, a significant increase in the total/HDL-cholesterol ratio and C-reactive protein, and a trend toward an impairment of carotid IMT and peak velocities were observed. In the patients in group B, the addition of GH to the standard replacement induced a significant increase in IGF-I levels together with a decrease in systolic and diastolic blood pressure, total cholesterol and total/HDL-cholesterol ratio, and C-reactive protein, and an increase in HDL-cholesterol levels with a trend toward an improvement of vascular parameters. At the end of the study, mean IMT was significantly lower than at baseline both in group A (from 0.88 +/- 0.28 to 0.85 +/- 0.27 mm, P = 0.0003) and in group B (from 0.83 +/- 0.21 to 0.80 +/- 0.20 mm, P = 0.003). In conclusion, 6 months of GH replacement has beneficial effects whereas 6 months of GH deprivation has detrimental effects on cardiovascular risk factors and atherosclerosis. These findings support the indication for GH replacement in severe GH deficiency adult patients.

The severity of growth hormone deficiency correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study.

In 100 patients with hypopituitarism and 80 sex- and age-matched healthy subjects, we correlated the severity of cardiac impairment to the severity of GH deficiency (GHD). By the GH peak after arginine plus GHRH test (normal > 16.5 microg/liter), the patients were classified as severe GHD (n = 56), partial GHD (n = 27), and non-GHD (n = 17). Compared with controls, decreased left ventricular ejection fraction at rest was found only in severe GHD patients (55.0 +/- 8.8 vs. 63.4 +/- 4.5%, P < 0.001); decreased left ventricular ejection fraction response on effort in severe (-4.6 +/- 17.4 vs. 15.2 +/- 9.1%, P < 0.001) and partial GHD patients (3.6 +/- 6.6 vs. 14.6 +/- 8.3%, P < 0.001); decreased diastolic filling at rest in severe (2.53 +/- 0.68 vs. 3.01 +/- 0.48 end-diastolic volume per second, P < 0.001) and partial GHD (2.61 +/- 0.45 vs. 2.89 +/- 0.54 end-diastolic volume per second, P = 0.004) patients; and decreased exercise duration and capacity in all the patient groups. A normal systolic performance on effort was found in 21.4% of severe GHD, 55.6% of partial GHD, all non-GHD, and 93.7% of controls. A normal diastolic filling at rest was found in 57.1% of severe GHD, 74.1% of partial GHD, 76.5% of non-GHD, and 90% of controls. In conclusion, cardiac performance is correlated with the GH status because significant impairment was found in patients with severe and partial GHD but not in non-GHD hypopituitary patients.

Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency.

OBJECTIVE: To investigate the role of IGF-1 on intima-media thickness (IMT) at common carotid arteries by Doppler ultrasonography. SUBJECTS: Thirty-nine patients (17 women, 22 men, aged 25-70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF-1 levels, and 39 sex-, age- and body mass index (BMI)-matched healthy controls. RESULTS: Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0.88 +/- 0.26 vs. 0.69 +/- 0.14 mm, P < 0.001), and systolic and diastolic peak velocity (P < 0.001) compared to controls. Eight patients (18%) and one control (2.1%, P = 0.04) had well-defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0.78, P < 0.001). In both controls (r = -0.82; P < 0.0001) and patients with GHD (r = -0.84, P < 0.0001), serum IGF-1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH-deficient patients were total cholesterol levels (t = 5.2, P < 0.001), followed by disease duration (t = 2.4, P = 0.02), while in controls the variables most significantly related to IMT were IGF-1 levels (t = -9.9, P < 0.001), followed by low density lipoprotein (LDL)-cholesterol levels (t = -2.3, P = 0.02). Compared to patients with normal IGF-1 levels, those with low IGF-1 levels had lower high density lipoprotein (HDL)-cholesterol levels (1.0 +/- 0.2 vs. 1.3 +/- 0.2 mmol/l, P = 0.0002), and higher glucose (54.3 +/- 6.1 vs. 48.9 +/- 5.9 mmol/l, P = 0.008), insulin (25.2 +/- 6.8 vs. 18.8 +/- 6.0 mUl/l, P = 0.004), total cholesterol (7.1 +/- 1.1 vs. 4.9 +/- 0.6 mmol/l, P < 0.0001), total/HDL-cholesterol ratio (7.2 +/- 1.8 vs. 3.9 +/- 0.7, P < 0.0001), fibrinogen levels (319.8 +/- 56.9 vs. 241.8 +/- 53.0 mg/dl, P < 0.0001) and mean IMT at common carotid arteries (1.05 +/- 0.25 vs. 0.69 +/- 0.07 mm, P < 0.0001). Atherosclerotic plaques were found only in GH-deficient patients with low IGF-1 levels. CONCLUSIONS: GH-deficient patients have alterations in lipid profile with an increase in the total/HDL-cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF-1 deficiency have increased IMT.

Somatostatin analogs in treatment of non-growth hormone-secreting pituitary adenomas.

Besides well-known effects in GH-secreting adenomas, somatostatin analogs such as octreotide and lanreotide have been used in TSH-secreting adenomas and in the so-called clinically nonfunctioning adenomas. The rationale for their use is based on the evidence that both these tumor types express large amounts of somatostatin receptor subtypes 2 and 5, which are preferentially bound by octreotide and lanreotide. However, whether in TSH-secreting adenomas the results are excellent in the nonfunctioning type, the results are controversial. Some preliminary results showing a very rapid recovery of the visual field have not been confirmed subsequently. No evident effect of tumor shrinkage has been reported. At present, the use of somatostatin analogs in clinically nonfunctioning adenomas is questioned.